This invention relates to a novel method of inducing and maintaining anesthesia while diminishing concomitant liability of adverse effects by the administration of (R)-isoflurane or (R)-desflurane and novel compositions of these compounds for use in the above disclosed novel method.
The active compounds of the method and composition of the present invention are optical isomers of the compounds isoflurane and desflurane.
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (-) and d and l are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy. However, its L-thalidomide counterpart was discovered to be a potent teratogen.
Isoflurane is 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether. It has the structural formula: ##STR1## Desflurane is 2-(difluoromethoxy)-1,1,1,2-tetrafluoroethane. It has the structural formula: ##STR2##
The racemic mixture forms of isoflurane and desflurane are general anesthetic drugs used to induce and maintain anesthesia. The state of anesthesia is a drug induced absence of perception of all sensations. General anesthesia is used most often during surgical procedures. Isoflurane, and desflurane are non-flammable liquids, administered by inhalation. This route of administration makes the effective dose and time course of action more predictable and more easily controlled.
Isoflurane has certain advantages over other general anesthetics such as halothane or ethrane. Its potency is between that of halothane and enflurane. Induction and recovery from anesthesia is more rapid with isoflurane than with halothane or ethrane however it is still slow. In addition, isoflurane is slightly less depressant to respiration and the cardiovascular system in the dog than either halothane or ethrane, however it still causes respiratory depression. Isoflurane shows significantly less sensitization of the heart to epinephrine induced arrhythmias than halothane. All commonly used muscle relaxants are markedly potentiated with isoflurane, the effect being most profound with the nondepolarizing type.
Desflurane, which is currently in clinical trials, also has certain clinical advantages over other anesthetic agents such as isoflurane. Scrips, 1481, pg. 27, (1990).
While isoflurane and desflurane have certain advantages over other anesthetic agents, they also have disadvantages which are primarily adverse effects which are in general dose dependent extensions of pharmacophysiologic effects of the compounds. These adverse effects include respiratory depression, hypotension, arrhythmias, shivering, nausea, vomiting, ileus, malignant hyperthermia, elevated white blood count and slow recovery from anesthesia. These adverse effects are primarily due to the high dose of the racemic mixture of isoflurane and desflurane needed to induce and maintain anesthesia.
It is therefore desirable to find a compound with the advantages of isoflurane and desflurane which would not have the above described disadvantages.